National Eye Institute 5R01EY035092-03

Cell-based therapies for retinal degeneration

The NIH grant funds a project at University of Colorado Denver to develop stem cell-derived retinal transplants to restore vision in patients with end-stage dry age-related macular degeneration by regenerating photoreceptor and RPE cells and assessing their integration and function.

Description

This project addresses the NEI Audacious Goal Initiative (AGI) of restoring vision through regeneration of photoreceptor cells and their connections. Among degenerative diseases of the outer retina amenable to regenerative therapies, dry age-related macular degeneration (AMD) is a major target. AMD is the leading cause of irreversible blindness in developed countries, with the dry form accounting for nearly 90% of patients affected by this condition. Patients with end-stage dry-AMD present macular photoreceptor and retinal pigment epithelium (RPE) atrophy, and there is no available treatment that can restore their lost vision. To address this unmet need, the project aims to devise novel cell-based transplantation strategies to jointly regenerate photoreceptor and RPE cells, and identify mechanisms supporting structural and functional integration of the transplanted cells. The study will establish the feasibility and mechanisms of structural and functional integration of a novel stem cell-derived 3D retinal transplant containing photoreceptors and RPE (3DNR/RPE) in a minipig model of end-stage macular atrophy. Preliminary results showed survival of the transplants within the subretinal space, with increased light response six weeks post-transplantation. The project will use multimodal in vivo ocular evaluation, ex vivo assessments, and non-invasive functional imaging to determine the extent of integration. Hypotheses include re-establishment of physiological interactions, synapse formation with host cells, increased light response, and light-triggered responses in bipolar and ganglion cells. The strategy involves generating retinal tissue transplants from hiPSC containing functional photoreceptors and RPE cells organized as in the native retina. The potential impact is to provide critical preclinical evidence supporting the feasibility of hiPSC-derived 3DNR/RPE transplants for cell-replacement therapy, potentially becoming the first solution for restoring vision in patients with end-stage dry-AMD.

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